Ischemia is a condition wherein the blood flow is completely obstructed or considerably reduced in localized parts of the body, resulting in anoxia, reduced supply of substrates and accumulation of metabolites. Although the extent of ischemia depends on the acuteness of vascular obstruction, its duration, tissue sensitivity to it, and developmental extent of collateral vessels, dysfunction usually occurs in ischemic organs or tissues, and prolonged ischemia results in atrophy, denaturation, and necrosis of affected tissues.
Ischemic cerebrovascular injury development mechanisms are classified into three types, thrombotic, embolic, and hemodynamic. The principal pathological condition for all three types is nevertheless cerebral ischemia, whose severeness and duration define the extent of cerebral tissue injuries. At the site of severe ischemia, nerve and endothelial cells rapidly suffer from irreversible injuries, forming typical infarction nidi due to necrosis. Although the bloodstream moderately declines and functions of neurocytes are suspended in the ischemic penumbra, their survival capacity is not lost and the remaining cerebrovascular system can recover its functions when circulation is resumed via collateral vessels.
In ischemic cardiopathy, which are diseases that affect the coronary artery and cause myocardial ischemia, the extent of ischemic myocardial cell injury proceeds from reversible cell damage to irreversible cell damage with increasing time of the coronary artery obstruction.
Drugs for preventing such cytopathy caused by ischemia or stimulating the regeneration of damaged cells may conceivably provide fundamental therapy of ischemic cerebral and cardiac disorders.
Based on this concept, drugs efficacious in preventing and treating neurocyte injury following the transient cerebral ischemia have been reportedly screened by injecting candidate substances for ischemic brain protective factors into the ventricle or peripheral blood vessel and studying the effect of the substances morphologically and functionally. For example, the intraventricular administration of prosaposin to Mongolian gerbils significantly relieved learning disability after ischemia, and pathological inspection of the hippocampal CA1 area revealed a remarkable increase of the number of pyramidal cells compared with the control (Sand, A. et al.: Biochem. Biophys. Res. Commun. 204: 994-1000, 1994). Like prosaposin, it has been proven that the intraventricular injection of ciliary neurotropic factor (CNTF) and interleukin-6 (IL-6) also significantly increased, in a dose-dependent manner, the number of pyramidal cells and synapses in the CA1 area (Wen, T-C et al.: Neurosci. Lett. 191: 55-58, 1995) (Matsuda, S. et al.: Neurosci. Lett. 204: 109-112, 1996). The intraventricular injection of basic fibroblast growth factor (bFGF) has also been reported to significantly protect against ischemic hippocampus, though not in the same way as prosaposin, CNTF and IL-6 (Wen, T-C et al.: Neuroscience, 65: 513-521, 1995). However, action mechanisms of these protective factors for ischemic brain disorders have not been clarified in detail.